An integrative multi-dimensional genetic and epigenetic strategy to identify aberrant genes and pathways in cancer

Here we show how multi-dimensional genomics data analysis would enable the deciphering of mechanisms that disrupt regulatory/signaling cascades and downstream effects. Since not all gene expression changes observed in a tumor are causal to cancer development, we demonstrate an approach based on multiple concerted disruption (MCD) analysis of genes that facilitates the rational deduction of aberrant genes and pathways, which otherwise would be overlooked in single genomic dimension investigations.Notably, this is the first comprehensive study of breast cancer cells by parallel integrative genome wide analyses of DNA copy number, LOH, and DNA methylation status to interpret changes in gene expression pattern. Our findings demonstrate the power of a multi-dimensional approach to elucidate events which would escape conventional single dimensional analysis and as such, reduce the cohort sample size for cancer gene discovery.Genomic analyses have substantially improved our knowledge of cancer. Gene expression profiling, for example, is utilized to delineate subtypes of breast cancer, and has facilitated the derivation of predictive and prognostic signatures [1-5]. However, not all of the gene expression changes observed are causal to cancer development, and global gene expression analysis alone cannot distinguish between causal and reactive changes. Corresponding alteration at the DNA level is regarded as evidence of causality; for example, gene deletion or gene silencing by methylation. Hence, examining genetic and epigenetic events in conjunction with the changes in gene expression pattern should improve the identification of causal changes that lead to disease phenotype.Analysis of gene copy number alone has correlated breast cancer genome features with poor prognosis based on the degree of genomic instability observed [6]. In terms of gene discovery, specific genomic regions containing important loci have been shown to be frequently gained or lost [7-11]. Integrative